Work from these laboratories indicates that the renal medulla exerts a non-excretory antihypertensive function mediated by the renomedullary interstitial cells (RIC). Moreover, it is proposed that the RIC exert this function by secreting substances that are absorbed and circulate in the manner of an antihypertensive hormone(s). The support for these proposals resulted from studies dealing with the perfusion of whole kidneys under different conditions (including uretero-venous anastomosis and ureteral ligation), the transplantation of fragmented renal medulla (Tr Med) and the transplantation of RIC grown in tissue culture (Tr TCric). From fresh frozen renal medulla and TCric antihypertnesive lipids can be extracted. These lipids exert an antihypertensive action almost identical to that of Tr Med and Tr TCric. It is suggested that the proposed antihypertensive renomedullary hormone (ARH) is present in the extracted lipids. The present proposal entails the following major features: 1) isolation and identification of the proposed ARH using both renal medulla and TCric; 2) identification of the mechanism of action of RIC and its proposed hormone to known prohypertensive actions of the kidney, especially the interplay of angiotensin and sodium-volume loads; 4) special studies dealing with RIC in culture, including their fractionation, isolation of PG and ARH synthetase system; identification of substances that stimulate and/or restrain the secretory capacity of RIC (tropic substances); 5) means of injuring RIC in culture and in vivo; and 6) the relationship of RIC and the proposed ARH to the vascular disease of hypertension. The isolation and identification of the proposed ARH, formerly termed ANRL, is considered of utmost importance since it would make available a potential therapeutic and/or prophylactic substance under natural feedback controls.